Polypeptides synthesized in the hypothalamus have been implicated in the control of hypophysiotrophic hormone release by the anterior pituitary. Recent evidence, however, has shown unequivocally that these polypeptides, referred to as releasing hormones or factors, have significant extrahypophyseal activity that is independent of their effect on the adenohypophysis. These observations have prompted speculation that the polypeptides, and particularly pyroglutamyl-histidyl-prolineamide (thyrotropin-releasing factor, or TRF), in fact may be brain neuroregulatory agents. Preliminary data obtained in our laboratory are in accord with this hypothesis, and specifically suggest that TRF may regulate brain catecholamine metabolism. We have demonstrated, for instance, that TRF directly inhibits the enregulatory role of TRF in brain and the specific regulatory role of TRF on catecholamine metabolism. Evaluation of the effects on catecholamine function will begin by investigating potential interactions of TRF on isolated portions of the metabolic pathways, including synthetic and degradative enzymes, uptake systems, and release mechanisms. These studies will serve as an essential preface to analysis of interactions in the living animal. The second portion of this proposal, while intimately related to the studies on catecholamine metabolism, will proceed independently. We reason that if TRF is a neuroregulatory agent, then TRF should possess metabolic characteristics similar to those of known neuroregulatory compounds. Thus, we will define the neuroanatomic distribution of TRF-containing cells by immunofluorescence, the subcellular distribution of TRF in various brain regions, the nature and localization of enzymes controlling its formation and destruction, and possible mechanisms responsible for its transport and storage in cells. While the specific effects of TRF are of immediate interest in this proposal, the overall significance of potential neuroregulatory roles of other central nervous system polypeptides may be of far greater import. BIBLIOGRAPHIC REFERENCES: Stolk, Jon M. and Peter C. Whybrow: Clinical and Experimental interrelationships between Sympathetic Nervous System Activity and Pituitary-thyroid function. Neuroendocrinology, 1976, in press.